Under healthy conditions, carbohydrates are converted after consumption to glucose, which is the body's primary source of energy. However, when the intake of carbohydrates is limited for a long enough period of time, or when the carbohydrate metabolism is disturbed, a point is reached where the body draws on alternative energy systems, fat or amino acid stores, for fuel. Upon catabolism of the lipids, several metabolites may be produced, like acetoacetate, acetone and β-hydroxybutyric acid, which metabolites are referred to as ketone bodies. These compounds serve as important metabolic fuels for many peripheral tissues, particularly heart and skeletal muscle, and in the absence of glucose, ketone bodies become the brain's major fuel sources.
When the formation of ketone bodies exceeds the mammal's capacity of treating them, the ketone bodies are accumulated in blood to cause ketonaemia. Conditions where the concentration of ketone bodies is high in urine are called ketonuria, and both of them are generally called ketosis. During ketosis or hyperketonaemia, ketone body levels in the blood become abnormally high. Severe ketosis may result in acidosis, a condition in which blood pH typically decreases below 7.3, the partial pressure of carbon dioxide (PCO2) in blood is below 30 mm Hg and bicarbonate levels in blood below 15 mm Hg. The symptoms of acidosis include malaise, weakness, anorexia and vomiting and these may eventually lead to coma and even death.
During a disturbed carbohydrate metabolism, as may occur during insulin resistance or during anaerobic conditions, pyruvate often is not sufficiently metabolised to Krebs cycle intermediates, but at least partially to lactic acid instead. Accumulation of the latter may occur on a local level, e.g. in tissue or muscle, wherein it will cause a metabolic disturbance of cell functioning and pain, or it may occur systemically which may lead to acidosis. Disturbed carbohydrate metabolism which leads to lactic acidosis can be associated with liver malfunction, either through liver damage or underdeveloped enzymatic functions therein, like may occur in part of the babies of young gestational age. In lactic acidosis, a condition in which lactate levels in the blood are typically above 2 mmol/l. It is common to make a distinction between hyperlactacidemia and severe lactic acidosis in terms of the lactate concentration in the blood, usually at about 5 mol/l.
In addition to lactic acidosis or ketoacidosis there is a group of organic acidurias (some 25-30 different types) that belongs to the group of metabolic acidoses, wherein an organic acid accumulates in the blood and urine.
Ketosis can occur due to high endogenous biosynthesis and/or imparted clearance or metabolism. Many people suffering from severe energy malnutrition or protein-energy malnutrition also experience a form of ketosis or from an even more severe form thereof, called ketoacidosis (ketone body blood levels above 7 mmol/l). Also diabetics suffer frequently from abnormal high levels of ketone bodies. Ketosis or even ketoacidosis can be caused by inborn or temporary metabolism errors, e.g. errors in branched chain metabolism, like in maple syrup disease, during inherited disorders in glycogen synthesis rate, or in persons having certain types of inherited errors in metabolism, e.g. persons suffering from propionic acidemia, isovaleric acidemia, methylmalonic acidemia, oxoacid coenzym A thiolase deficiency or deficiencies in the activity of other thiolases, and persons having an underdeveloped metabolic system like infants of young gestational age.
Ketosis can also play a role in persons suffering from hyperglycaemia, which is a metabolic state of the body wherein glucose levels in blood are increased compared to normal concentrations. Yet, despite these high blood glucose levels, cells “starve” since the insulin-stimulated glucose entry into cells is somehow impaired. Examples of persons suffering from hyperglycaemia are those which are diagnosed to suffer from the so-called metabolic syndrome or syndrome X, obesity and several types of diabetes, like type I, type II and gestational diabetes. Especially those persons suffering from an imparted insulin-release or from “insulin resistance”, will frequently develop a ketosis state.
Long term hyperglycaemia resulting from disturbed carbohydrate metabolism will result in increased formation of undesired advanced glycation products (AGE) by interaction between reactive amino groups in proteins, like primary amino groups such as those occurring in lysine, and in particular aldehydes, e.g. those resulting from reducing sugars. In this way carboxymethylated lysines are formed. Maillard-type reactions of endogenous proteins like enzymes and structural proteins impart their function which results in undesired loss of function of the total organ or tissue. These complications are in particular cardiovascular problems, like macro- and micro-angiopathy, problems with the liver, pancreas, kidney, skin, the eye but also embryopathy during pregnancy are often observed in diabetics and some of them also in the aged population.
Where ketosis is caused by an impaired glucose metabolism, it is often treated by administering insulin or a sugar, such as glucose, xylitol, or the like. However, as discussed above, ketosis is not always associated with a disordered glucose metabolism or AGE formulation, and where a relation exists, the effect of these sugars and insulin on the reduction of the concentration of ketone bodies is often transitory and lasts only a short period of time.
Hyperlactacidemia can be due to a disorder in cellular respiration, abnormalities in the activity of pyruvate dehydrogenase, the Krebs cycle, the respiratory chain or due to liver function problems including disorders in glycogen metabolism, gluconeogenesis and fatty acid oxidation. Lactic acidemias can also be observed during chronic infections, in particular of the urinary tract, chronic diarrheas and tissue hypoxias as may occur during ischaemic events like those that are applied during surgery or traumatic experiences where blood supply is interrupted, but also in underdeveloped metabolic or anatomical systems like in part of the neonates. During hyperlactacidemia the weight ratio of lactate to pyruvate in blood preprandially will typically be above 0.35:1. It can be observed in a variety of acquired circumstances including infections, severe catabolism, organ dysfunction and tissue ischaemia, but also during some inherited metabolic disorders. It is a common disease symptom in pediatrics. Ketonuria, hyperlactacidemia and hyperammonemia, but also abnormal values of pyruvate, glucose, blood gases, electrolytes and pH are important indicators of the metabolic situation of the patient.
A need exists for a nutritional preparation, supplement or a dietetic regimen for the prevention or treatment of metabolic disorders associated with elevated concentrations of ketone bodies and/or lactate in blood, and/or advanced glycation products and/or Maillard products in tissue in a mammal. Preferably consumption of the nutritional preparation or supplement should be easy to comply with, because of its enjoyable organoleptic properties, it should fit in normal day life and feeding/drinking practices and should have no undesired side effects.
Neonates and in particular preterm babies often suffer from underdeveloped metabolic systems, which need to adapt in a short time to a new nutritional regimen. During the first few days and even weeks dramatic changes occur in their body for example with regard to expression of enzymes, organ capacity e.g. of the liver, pancreas, gut and kidneys and gut content. When nutritional practices are not adapted to their metabolic capabilities, disorders and diseases can be observed such as abnormally high or low levels of lactate, ketone bodies, ammonia and pH in the blood, which often require medical intervention.
Ketones may also be formed when high amounts of lipids or excess branched chain amino acids are consumed. In particular when consuming complete nutritional formulae in which lipids provide more than 40 energy percent for adults, or even more than 52 en % for premature infants, ketones can be formed. The same problem occurs when in complete nutritional formulae the amount of branched chain amino acids is high, e.g. more than 24 g/100 g amino acids, or even more than 26 g. Complete nutritional products for adult people provide per daily dose more than 80 g protein and more than 1800 kcal. For premature infants complete nutrition provides per daily dose 6 g protein and 225 kcal energy.
An inverse correlation between blood total ketone body and alanine concentrations has been reported in the art. Nosadini, R. et al. published in Biochem J (1980), 190, 323-332 a model study in rats wherein it is demonstrated that after consumption of high doses of alanine blood levels of ketone bodies were decreased. Its positive effect was attributed partly to the enhanced oxaloacetate availability, which in turn was thought to result in enhanced citrate formation and decreased intramitochondrial acetyl-CoA availability for ketogenesis.
This effect was partially mimicked by using extremely high doses of 6 mmol (=0.69 g) of aspartate per kg body weight per hour to 48-hours starved rats, whereas half a dosis did not yield any significant effect on blood ketone body concentrations. It is clear that in humans weighing 70 kg equivalent doses of about 193 g aspartate per day would impart consumption of the normal diet heavily and put high demands on willingness to comply by the patient.